EFFECTS OF RECOMBINANT HUMAN STEM CELL FACTOR ON HEMATOPOIESIS

重组人干细胞因子对造血的影响

• 批准号: 6116371
• 负责人: ROBERT GOFF ANDREWS
• 金额: $ 8.67万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6116371
• 关键词: Mammalia; Primates; animal tissue; biotechnology; hematology; lymphatic system; transplantation

The goal of this project is to study the in vivo and in vitro biological effects on hematopoiesis of recombinant human stem cell factor (rhSCF), a ligand for the human c-kit molecule, a cell surface receptor with tyrosine kinase activity. In vitro, SCF by itself stimulates little proliferation of human and baboon marrow hematopoietic colony-forming cells (CFC), but does have stimulating effects when combined with other hematopoietic growth factors, including IL-3, G-CSF, GM-CSF, and Epo. In vivo, SCF stimulates a dose-dependent leukocytosis, with increases in neutrophils, monocytes, eosinophils, basophils, and T and B lymphocytes in the blood. SCF also stimulates a reticulocytosis and increases in the numbers of red blood cells and in hematocrit. In marrow, SCF stimulates a dose-dependent increase in cellularity and morphologically immature erythroid and granulocytic cells. Importantly, SCF increases the number of hematopoietic colony-forming progenitor cells in marrow and blood. The number of progenitor cells in blood increases from 10-fold to >1000-fold in animals given SCF at a dose of 200 g/Kg/day, with an associated increase in numbers of CD34+ cells in blood. We have also shown that transplantable cells capable of rescuing and reconstituting lymphohematopoiesis in lethally irradiated baboons are increased in the blood by treatment with high doses of SCF. SCF also has in vivo synergy with G-CSF. SCF at 25 g/kg/day, which alone does not stimulate a leukocytosis or an increase in peripheral blood progenitors, when administered with G-CSF increases the rate at which circulating WBC increase as well as the maximum WBC achieved, compared with G-CSF alone. Most importantly, this dose of SCF when combined with G-CSF dramatically enhances the circulation of progenitor cells as well as marrow repopulating cells compared with G-CSF alone. Animals transplanted with blood cells collected during stimulation with the combination of SCF plus G-CSF engraft much more rapidly than do animals transplanted with cells collected during stimulation with G-CSF alone. Studies are in progress to determine if SCF, in combination with other growth factors, can be used to expand the number of progenitors from marrow and blood in vitro and if these expanded cells can engraft lethally irradiated baboons.

该项目的目的是研究重组人干细胞因子造血（RHSCF）的体内和体外生物学作用，这是人类C-KIT分子的配体，该分子是具有酪氨酸激酶活性的细胞表面受体。 在体外，SCF本身几乎没有刺激人和狒狒骨髓造血菌落形成细胞（CFC）的增殖，但与其他造血生长因子（包括IL-3，G-CSF，GM-CSF，gm-CSF和EPO）相结合时确实具有刺激作用。在体内，SCF刺激剂量依赖性的白细胞增多，随着血液中嗜中性粒细胞，单核细胞，嗜酸性粒细胞，嗜酸性粒细胞，嗜酸性粒细胞，T和B淋巴细胞的增加。 SCF还刺激了网状细胞增多症，并增加了红细胞和血细胞比容的数量。 在骨髓中，SCF刺激细胞性剂量依赖性增加，形态学不成熟的红细胞和粒细胞细胞。重要的是，SCF增加了骨髓和血液中造血菌落形成的祖细胞的数量。 血液中的祖细胞数量从动物中以200 g/kg/天的剂量从10倍增加到> 1000倍，与血液中CD34+细胞的数量有关。 我们还表明，通过高剂量的SCF治疗，血液中充满辐照的狒狒的淋巴结瘤的移植细胞在血液中增加了。 SCF还与G-CSF具有体内协同作用。 与单独使用G-CSF相比，当使用G-CSF施用时，仅刺激白细胞增多或外周血祖细胞增长的SCF，仅刺激白细胞增多或外周血祖细胞增长，而循环WBC的增加以及获得的最大WBC的速率与单独的G-CSF相比。 最重要的是，与单独使用G-CSF相比，与G-CSF结合使用时，这种SCF剂量会大大增强祖细胞的循环以及骨髓再现细胞的循环。 在刺激过程中收集的血细胞移植的动物与SCF加G-CSF的组合相比，与单独使用G-CSF刺激期间收集的细胞移植的动物相比，动物的植入速度要快得多。正在进行研究以确定SCF是否与其他生长因子结合使用，可以用于扩大体外骨髓和血液的祖细胞的数量，以及这些扩展的细胞是否可以植入致命的辐照狒狒。